Antiangiogenic agent (TNP-470) inhibition of ectopic bone formation induced by bone morphogenetic protein-2.
Bone morphogenetic protein (BMP) is a potent inducer of ectopic bone formation, and TNP-470, a synthetic analog of fumagillin, is an antiangiogenic agent that strongly inhibits neovascular formation in vivo. We investigated the effects of TNP-470 on BMP-induced ectopic bone formation to clarify the role of angiogenesis in bone formation. Collagen pellets containing recombinant human BMP-2 (rhBMP-2) were implanted beneath the fasciae of dorsal muscles in mice. By daily subcutaneous administration of TNP-470, ectopic new bone formation was inhibited in a dose-dependent manner. Histological examination revealed that TNP-470 prevented proliferation of mesenchymal cells and chondrogenesis at the initial step of endochondral bone formation. Immunohistochemical staining with a specific antibody against bone morphogenetic protein type IA receptor showed that TNP-470 reduced the number of receptor-positive cells surrounding the BMP pellets. The inhibitory effect of TNP-470 on bone formation continued during the period of its administration, and discontinuation of treatment was followed by the resumption of the whole process of endochondral bone formation. This study showed that TNP-470 reversibly inhibits the biological activity of rhBMP-2 in the early stage of bone induction, suggesting that angiogenesis may play an essential role in the recruitment of BMP-receptor-positive cells that can respond to rhBMP-2 and differentiate into chondrocytes and/or osteoblasts.
Mori
S
S
Department of Orthopaedic Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Japan.
Yoshikawa
H
H
Hashimoto
J
J
Ueda
T
T
Funai
H
H
Kato
M
M
Takaoka
K
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001846:Bone Development / Q000187:drug effects*; D055396:Bone Morphogenetic Protein 2; D052005:Bone Morphogenetic Protein Receptors, Type I; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors*; D002454:Cell Differentiation / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects; D003510:Cyclohexanes; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008648:Mesoderm / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D018482:Muscle, Skeletal; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D010012:Osteogenesis / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000032:analysis / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D016212:Transforming Growth Factor beta
D000903:Antibiotics, Antineoplastic; C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D003510:Cyclohexanes; D004343:Drug Implants; D017978:Receptors, Growth Factor; D011994:Recombinant Proteins; D012717:Sesquiterpenes; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2; D017346:Protein Serine-Threonine Kinases; C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I; D000077609:O-(Chloroacetylcarbamoyl)fumagillol